Impaired Protein Quality Control During Left Ventricular Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor

Circ Heart Fail. 2017 Dec;10(12):e004252. doi: 10.1161/CIRCHEARTFAILURE.117.004252.


Background: Sustained inflammation in the heart is sufficient to provoke left ventricular dysfunction and left ventricular remodeling. Although inflammation has been linked to many of the biological changes responsible for adverse left ventricular remodeling, the relationship between inflammation and protein quality control in the heart is not well understood.

Methods and results: To study the relationship between chronic inflammation and protein quality control, we used a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (tumor necrosis factor; Myh6-sTNF). Myh6-sTNF mice develop protein aggregates containing ubiquitin-tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in Myh6-sTNF mice, which were also seen in tissue from patients with end-stage heart failure. Moreover, there was evidence of impaired autophagosome clearance after chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mammalian target of rapamycin complex 1 (mTORC1) activation, which has been linked to inhibition of both the proteasome and autophagy.

Conclusions: Myh6-sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.

Keywords: autophagy; inflammation; myocarditis; tumor necrosis factor; ubiquitin.

MeSH terms

  • Animals
  • Autophagosomes / enzymology
  • Autophagosomes / pathology
  • Autophagy
  • Cardiomyopathy, Dilated / enzymology*
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Heart Failure / enzymology
  • Heart Failure / pathology
  • Heart Ventricles / enzymology*
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Humans
  • Inflammation Mediators / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Transgenic
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Myosin Heavy Chains / genetics
  • Phenotype
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Time Factors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitination
  • Up-Regulation
  • Ventricular Dysfunction, Left / enzymology*
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / pathology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left*
  • Ventricular Remodeling*


  • Inflammation Mediators
  • Myh6 protein, mouse
  • Protein Aggregates
  • Tumor Necrosis Factor-alpha
  • Mechanistic Target of Rapamycin Complex 1
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Myosin Heavy Chains